• Rituxan® (rituximab)
† Phase 2 study intended to support an accelerated approval marketing application with the FDA
‡ Study arm to be initiated under clinical collaboration with Beigene, Ltd.
ME-401 is MEI’s wholly owned, selective, oral inhibitor of PI3K delta. We are commencing a Phase 2 study of ME-401 to support accelerated approval with the U.S. Food and Drug Administration in patients with relapsed or refractory follicular lymphoma (“FL”).
Clinical data presented from a Phase 1b clinical study at the American Society of Clinical Oncology (“ASCO”) 2018 Annual Meeting demonstrated class-leading efficacy: a 90% objective response rate was observed in patients with relapsed/refractory FL, chronic lymphocytic leukemia (“CLL”) and small lymphocytic lymphoma (“SLL”). The data suggest ME-401 may hold best-in-class potential as a PI3K delta inhibitor and its clinical profile presents opportunities to address a range of B-cell malignancies as a single-agent or in combination with other cancer treatments.
MECHANISM OF ACTION
The PI3K/AKT/mTOR pathway is an important signaling pathway for many cellular functions such as cell survival, cell cycle progression and cellular growth. PI3Ks are a family of enzymes within this pathway that have been shown to play a critical role in the proliferation and survival of certain cancer cells. There are several isoforms of PI3K that are expressed in different types of cells. The PI3K delta isoform is believed to be important for survival of certain B-cell leukemias and lymphomas.
ABOUT B-CELL MALIGNANCIES
B-cell malignancies are those starting in B lymphocytes, a type of white blood cell. They include both slow growing (indolent) diseases as well as aggressive diseases and represent a collection of different blood cancers. Examples include chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma.
Phase 1b Study
ME-401 is being evaluated in an ongoing Phase 1b dose escalation study in patients with relapsed or refractory follicular lymphoma and other B-cell malignances. At the 2018 ASCO Annual Meeting, we reported data indicating that ME-401 administered as a single-agent achieved a high response rate of 90% among 30 evaluable patients as well as a high response rate of 86% in the group of 21 patients with FL. ME-401 was generally well-tolerated. No dose-limiting toxicities were identified at any dose level. Among the most common adverse events, Grade 3 adverse events of interest were diarrhea 19%, rash 13%, colitis 6% and stomatitis 3%. An expansion cohort of up to 30 patients with FL, CLL and SLL was added to further evaluate the safety and efficacy of ME-401 as a single agent at the 60 mg dose. An additional 15 patients are enrolled in a study arm evaluating ME-401 (60 mg) in combination with rituximab (marketed as Rituxan®) in patients with various B cell malignancies.
Additionally, in October of 2018 we announced a clinical collaboration with BeiGene, Ltd. In connection with the BeiGene collaboration we will amend the ongoing Phase 1b trial to evaluate the safety and efficacy of ME-401 in combination with BeiGene’s zanubrutinib, an investigational BTK inhibitor, in patients with B-cell malignancies.
Phase 2 Study to Support Accelerated Approval with U.S. FDA
ME-401 is progressing into a Phase 2 study to support accelerated approval by the U.S. Food and Drug Administration. The study will be a global, randomized, trial evaluating the efficacy, safety, and tolerability of ME-401 in patients with follicular lymphoma after failure of at least two prior systemic therapies including chemotherapy and an anti-CD20 antibody. Two ME-401 single agent dosing regimens will be evaluated; in one arm, ME-401 will be administered 60 mg once daily continuously and in the other arm, ME-401 will be administered 60 mg once daily continuously for two cycles (that is, for eight weeks) followed by an intermittent schedule in which ME-401 will be administered 60 mg once daily for the first seven days of a 28 day cycle followed by three weeks with 60 mg placebo. Approximately 150 patients will be randomized in the study and the primary efficacy endpoint will be the rate of objective response to therapy.
This two-arm study design allows further evaluation of the dosing regimen from the Phase 1b study, while additionally permitting exploration of an intermittent dosing regimen. Our data from the ongoing Phase 1 b study suggests that an intermittent schedule may retain the ability to deliver the class-leading levels of efficacy observed in the ongoing Phase 1b study, but with fewer adverse events than observed to date with continuous dosing.
While continuous dosing regimen represents an important opportunity to provide a new treatment for patients with B-cell malignancies, the intermittent schedule may demonstrate an enhanced clinical profile and thereby increase the utility of ME-401 as a monotherapy and in combination with other cancer treatments.
- Phase 1 Clinical Study
- Commencing Year-end 2018: Phase 2 Clinical Study to Support Accelerated Approval